Structural Refinement of Glucagon for Therapeutic Use.

Glucagon counters insulin's effects on glucose metabolism and serves as a rescue medicine in the treatment of hypoglycemia. Acute hypoglycemia, a common occurrence in insulin-dependent diabetes, is the central obstacle to correcting high blood glucose, a primary cause of long-term microvascular complications. As a result, there has been a resurgence of interest in improved glucagon therapy, including nonconventional liquid formulations, alternative routes of administration, and novel analogs with optimized biophysical properties.

Three-chain insulin analogs demonstrate the importance of insulin secondary structure to bioactivity.

This report describes the chemical synthesis and biological characterization of novel three-chain insulin analogs with a destabilized secondary structure. The analogs, obtained by chemical synthesis via a single-chain precursor and selective enzymatic digestion, were used to investigate the role of the highly conserved 'insulin fold'. Biological characterization through in vitro biochemical signaling showed extremely low activity at each insulin receptor when compared with native insulin.

Direct control of brown adipose tissue thermogenesis by central nervous system glucagon-like peptide-1 receptor signaling.

We studied interscapular brown adipose tissue (iBAT) activity in wild-type (WT) and glucagon-like peptide 1 receptor (GLP-1R)-deficient mice after the administration of the proglucagon-derived peptides (PGDPs) glucagon-like peptide (GLP-1), glucagon (GCG), and oxyntomodulin (OXM) directly into the brain. Intracerebroventricular injection of PGDPs reduces body weight and increases iBAT thermogenesis. This was independent of changes in feeding and insulin responsiveness but correlated with increased activity of sympathetic fibers innervating brown adipose tissue (BAT).

Optimization of the native glucagon sequence for medicinal purposes.

Background: Glucagon is a life-saving medication used in the treatment of hypoglycemia. It possesses poor solubility in aqueous buffers at or near physiological pH values. At low and high pH, at which the peptide can be formulated to concentrations of a milligram or more per milliliter, the chemical integrity of the hormone is limited, as evidenced by the formation of multiple degradation-related peptides.